The Mechanism of Inflammation-mediated Olfactory Dysfunction in Chronic Rhinosinusitis

 描述(申请人提供)：嗅觉丧失通常发生在慢性鼻-鼻窦炎(CRS)患者中，并对生活质量和患者安全产生重大影响。CRS嗅觉丧失背后的病理生理学机制尚不清楚，但动物模型表明，慢性炎症是CRS的一个标志，可能导致成熟或功能性嗅觉神经元的丧失，并抑制嗅神经元的再生。CRS导致炎症细胞大量涌入，多种促炎细胞因子水平升高，包括肿瘤坏死因子-α、IL-1β、IL-6、IL-17和干扰素-γ。特别是，这些细胞因子有可能对神经元再生和神经发生过程进行负面调节，这两者都可能导致功能性神经元的一过性或永久性丧失。这些再生通路的抑制通常是通过以下几个方面的综合作用来实现的：1)对神经细胞迁移或分化的影响，2)抑制神经前体细胞的增殖，或3)诱导神经前体细胞的死亡或凋亡。这一建议的中心假设是，神经毒性促炎细胞因子在CRS中过度表达，细胞因子表达和功能的改变有助于CRS相关的炎症和嗅觉丧失。我们将使用人类来源的嗅觉组织来验证这一假设，包括直接评估促炎细胞因子对嗅神经元和神经前体细胞的影响的机制研究。目的1将评估神经毒性细胞因子在人类嗅觉组织中的表达，并确定细胞因子的表达是否与嗅觉功能的客观指标相关。目的2将确定促炎细胞因子受体是否在人类嗅神经元和神经前体细胞上表达，并将评估单个细胞因子对细胞增殖、分化和凋亡等细胞过程的影响。我们假设，促炎细胞因子通过嗅神经元和神经前体细胞上表达的同源受体发挥作用，负向调节嗅神经元的存活和再生。这项研究的结果将有助于深入了解CRS中观察到的嗅觉功能障碍的机制，并可能有助于确定选择性治疗CRS相关性嗅觉丧失的特定治疗靶点。

 DESCRIPTION (provided by applicant): Loss of the sense of smell commonly occurs in patients with chronic rhinosinusitis (CRS) and has major impacts on quality of life and patient safety. The pathophysiology behind the olfactory loss observed in CRS is not clearly understood, but animal models suggest that chronic inflammation, a hallmark of CRS, may result in a loss of mature or functional olfactory neurons and an inhibition in olfactory neuron regeneration. CRS results in an influx of inflammatory cells and elevated levels of multiple pro-inflammatory cytokines, including TNF-α, IL-1β, IL-6, IL-17, and IFN-γ. These cytokines, in particular, have the potential to negatively modulate neuronal regeneration and the process of neurogenesis, both of which can cause transient or permanent loss of functional neurons. Inhibition of these regenerative pathways is typically mediated through a combination of: 1) effects on neuronal cell migration or differentiation, 2) Inhibition of neuronal progenitor cell proliferation, or 3) induction of neuronal progenitor cell death or apoptosis. The central hypothesis of this proposal is that neurotoxic pro-inflammatory cytokines are overexpressed in CRS and that alteration in cytokine expression and function contributes to CRS-related inflammation and olfactory loss. We will test this hypothesis using human-derived olfactory tissue, including mechanistic studies that directly assess the effect of pro-inflammatory cytokines on olfactory neurons and neuronal progenitor cells. Aim 1 will assess the expression of neurotoxic cytokines in human olfactory tissue and determine whether cytokine expression correlates with objective measures of olfactory function. Aim 2 will determine whether receptors for pro-inflammatory cytokines are expressed on human olfactory neurons and neuronal progenitor cells and will assess the effects of individual cytokines on cellular processes such as proliferation, differentiation, and apoptosis. We hypothesize that pro-inflammatory cytokines, acting through cognate receptors expressed on olfactory neurons and neuronal progenitor cells, negatively modulate olfactory neuron survival and regeneration. Findings from this study will provide insight into the mechanisms of olfactory dysfunction observed in CRS and may help to identify specific therapeutic targets for the selective treatment of CRS-associated olfactory loss.